Yarmolinsky James, Berryman Katie, Langdon Ryan, Bonilla Carolina, Davey Smith George, Martin Richard M, Lewis Sarah J
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Cancer Causes Control. 2018 Nov;29(11):1073-1080. doi: 10.1007/s10552-018-1081-5. Epub 2018 Oct 10.
Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies. We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer.
A genetic instrument was constructed using five single-nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (n ≤ 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls).
We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI 0.63-1.08; p = 0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI 0.57-1.70; p = 0.93).
Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.
观察性研究表明，膳食钙和血清钙是前列腺癌的危险因素。然而，此类研究存在残余混杂因素（由于未测量或测量不准确的混杂因素），影响了因果推断。孟德尔随机化利用随机分配（因此无混杂且在疾病发生前）的种系基因变异来替代表型，并加强观察性研究中的因果推断。我们检验了血清钙与总体及晚期前列腺癌风险增加相关的假设。
在一项全基因组关联研究（n≤61,079）中，利用与血清钙密切相关的5个单核苷酸多态性构建了一个基因工具。然后，该工具被用于检验血清钙升高0.5mg/dL（1个标准差，SD）对PRACTICAL（前列腺癌协会基因组癌症相关改变研究组）联盟中72,729名男性患前列腺癌风险的影响（44,825例病例，27,904例对照），以及对33,498名男性患晚期前列腺癌风险的影响（6,263例病例，27,235例对照）。
我们发现血清钙对前列腺癌风险有保护作用的证据较弱（钙每增加0.5mg/dL的比值比[OR]：0.83, 95%可信区间0.63 - 1.08；p = 0.12）。我们没有发现血清钙对晚期前列腺癌有影响的有力证据（钙每增加0.5mg/dL的OR：0.98, 95%可信区间0.57 - 1.70；p = 0.93）。
我们的孟德尔随机化分析不支持血清钙会增加总体或晚期前列腺癌风险的假设。
